Gregg C. Sylvester, MD, MPH

ACIP Meeting 

Pregnancy Outcomes with ccIIV4 

(Flucelvax); Post Marketing Study

October 25, 2023
2

Study Overview

Purpose Post-marketing commitment

Main Objective Evaluate specific pregnancy and fetus/infant outcomes

Study Design Prospective, observational safety study

Study Population Patients immunized with ccIIV4 as part of routine obstetrical care

Scientific 

Oversight 

Committee

Teratologist, blinded to exposure timing, reviewed and classified 

reported malformations using the MACDP criteria

Independent experts in maternal-fetal medicine, pediatrics, 

clinical research, infectious disease, epidemiology, and teratology 

reviewed safety data and aligned on malformation classification(s)

MACDP, Metropolitan Atlanta Congenital Defects Program; OB/GYN,ccIIV4, cell-based quadrivalent influenza vaccine (Flucelvax)
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Outcomes

Pregnancy Outcomes

• Live birth

• Stillbirth:

• Fetal death occurring ≥20 weeks’ 

gestation, or if gestational age was 

unknown, a fetus that weighed 500 gm 

or more

• Spontaneous abortion:

• Fetal death <20 weeks’ gestation, 

including missed abortion, incomplete 

abortion, and inevitable abortion

• Elective termination

• Voluntary interruption of pregnancy, 

including pregnancy termination that 

occurred electively, to preserve 

maternal health, or due to fetal 

abnormalities

Events of Interest

• Preterm birth:

• A live-born infant born at gestational 

age <37 weeks

• Low birth weight:

• A live-born infant whose birth weight is 

<2500 gm

• Major Congenital Malformation:

• Any major structural or chromosomal 

defect or combination of three or more 

conditional defects in live- or stillborn 

infants, or fetal losses of any 

gestational age, including outcomes 

prior to 20 weeks’ gestation or 

weighing <500 gm
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Eligibility/Ineligibility Criteria

Eligible Cases:

• Pregnant patients were enrolled prospectively 

• Sufficient information to confirm that vaccination with ccIIV4 

occurred during routine obstetrical care 

• HCP’s contact information to allow for follow-up

• Subjects may have self-enrolled or may have been enrolled by a 

participating OB/GYN clinic after providing informed consent

Ineligible Cases: 

• Retrospective cases

• Persons who had prior knowledge of an adverse pregnancy 

outcome

HCP - healthcare professional; OB/GYN - obstetrics and gynecology; ccIIV4 - cell-based quadrivalent influenza vaccine.
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Study Enrollment Over Three US Influenza Seasons

Persons Enrolled

2017/2018 10 

2018/2019 268

2019/2020 415

Total Enrolled 693

Lost to Follow-up (27)

Ineligible (1)

Primary Analysis Population 665
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Demographics

Primary analysis population (PAP)

Maternal age at conception (years) N=665 

Mean (SD) 28.0 (5.3)

Median 28.0

Min, max 17, 45

Paternal age at enrollment (years) N=612

Mean (SD) 30.4 (6.2)

Median 30.0

Min, max 17, 59

Ethnicity n (%) N=665

Hispanic or Latino 44 (6.6%)

Not Hispanic or Latino 437 (65.7%)

Missing* 184 (27.7%)

Race n (%) N=665

White 399 (60.0%)

Black or African American 194 (29.2%)

Asian 29 (4.4%)

American Indian or Alaskan Native 1 (0.2%)

Native Hawaiian or Other Pacific Islander 2 (0.3%) 

Other 28 (4.2%)

Unknown 12 (1.8%)

SD, standard deviation *One clinic did not report ethnicity.
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Baseline Characteristics

Primary analysis population (PAP)

Pre-Pregnancy BMI (kg/m2) N=661

Mean (SD) 29.6 (8.2)

Median 28.1

Min, max 15.0, 64.8

Number of previous pregnancies, n (%) N=665

0 195 (29.3%)

1 186 (28.0%)

2 135 (20.3%)

≥3 149 (22.4%)

Family history of congenital malformations, n (%) N=665

Offspring 8 (1.2%)

Maternal history 40 (6.0%)

Paternal history 40 (6.0%)

Any family history 78 (11.7%)

Any concurrent condition, n (%) 527 (79.2%)

Any concomitant medications, n (%) 651 (97.9%)

Substance use, n (%)

Any tobacco use 84 (12.6%)

Any alcohol use 1 (0.2%)

Any illicit drug use N/A

BMI, body mass index; N/A, not applicable; SD, standard deviation
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Exposure by Gestational Age

0

5

10

15

20

25

30

35

40

45

0 5 10 15 20 25 30 35 40 45

Number of exposures

Gestational age at exposure (weeks)

First trimester Second trimester Third trimester

Number of patients by gestational age at exposure to ccIIV4 (in weeks)

Among all subjects identified (N=693)

ccIIV4, cell-based quadrivalent influenza vaccine.
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Results: Pregnancy Outcomes

Outcome

Vaccine Exposure

Overall

First Trimester Second Trimester Third Trimester

Primary Analysis 

Population n=178 n= 277 n= 210 n=665

Live Birth, n

% (95% CI)

172

96.6% (92.8-98.8)

277

100% (98.7-100)

210

100% (98.3-100)

659

99.1% (98.0-99.7)

Stillbirth 0

0 (0.0-2.1)

0

0 (0.0-1.3)

0

0 (0.0-1.7)

0

0 (0.0-0.6)

Enrollment <20 weeks 

gestation n=147 n= 64 N/A n=211

Spontaneous Abortion* 4

2.7% (0.7-6.8)

0

0 (0.0-5.6) N/A 41.9% (0.5-4.8)

Elective Termination* 1

0.7% (0.0-3.7)

0

0 (0.0-5.6) N/A 10.5% (0.0-2.6)

*Calculated using the population enrolled at <20 weeks of gestation (n = 211) as the denominator.
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Results: Events of Interest

10.2

8.3

2.8

9.2

5.8

1.9

0

2

4

6

8

10

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Preterm birth Low birthweight Major Cong. Malformations

Percentage of events of interest (95% CI)

US prevalence (%) Study prevalence (%)

CDC, Centers for Disease Control and Prevention; CI, confidence interval; MACDP, Metropolitan Atlanta Congenital Defects 

Program; MCM, major congenital malformation; NCHS, National Center for Health Statistics; NVSS, National Vital Statistics System. 

1. Martin JA, et al. NCHS Data Brief. 2020;387:1–8; 2. Martin JA, et al. Natl Vital Stat Rep. 2019;68:1–47; 3. Correa A, et al. Birth Defects 

Res A Clin Mol Teratol. 2007;79:65–93.
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Results: Major Congenital Malformations

Timing of Vaccine/

Weeks GA Preferred MACDP term 

Trimester of Vaccine

First

5.4 Sex chromosome – XYY 

10.7 Talipes equinovarus

Second

16.1 Renal agenesis, right

16.1 Polycystic kidneys *

16.4 Clubfoot, cardiomegaly, aorta malformation 

(unknown), hypoplasia of upper or lower limb

18.1 Situs inversus abdominus

19.9 Hirschsprung’s Disease

23.0 Fluid around kidneys 

24.9 Micropenis, microphthalmos

Third

30.3 Transposition of great vessels

32.1 Trisomy 21, atrial septal defect, patent ductus 

arteriosus

33.0 Absent foreskin

33.3 Hypospadias

33.4 Absent forearm

GA – Gestational Age, MACDP - Metropolitan Atlanta Congenital Defects Program

*One infant who died 24h after birth had polycystic kidneys and fetal anhydramnios reported during pregnancy. 

Key:

Defect with known cause

No temporal association

Unable to assess temporality 
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Strengths and Limitations

Strengths

• >660 Subject enrolled across 

multiple influenza seasons

• Diverse population which 

included racial and ethnic groups 

as well as a broad range of 

maternal ages

• Enrollment occurred at five study 

sites in four states

Limitations

• Effect of potential confounders 

(previous pregnancy outcomes, 

pregnancy complications, etc.) 

• Potential for missing data or 

limited level of detail collected as 

part of routine care 

• MACDP counts MCMs detected 

up to the age of 6 years

MACDP - Metropolitan Atlanta Congenital Defects Program, MCM – Major Congenital Malformations
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Conclusion

• The findings are consistent with published data from various 

databases and surveillance systems that monitor the safety of 

influenza vaccines1–5

• The independent expert committee found no evidence of a safety 

concern 

• These data support the use of ccIIV4 for immunization against 

influenza in this population

1. Chambers CD, et al. Vaccine. 2016;34(37):4443–4449; 2. Zerbo O, et al. Vaccine. 2017;35(24):3186–3190; 3. Donahue JG, et al. 

Vaccine. 2019;37(44):6673–6681; 4. Moro P, et al. Drug Saf. 2017;40(2):145–152; 5. Louik C, et al. Vaccine. 2016;34(37):4450-4459.